Phenoxy-alkyl-carboxylic acid derivatives and the preparation thereof

ABSTRACT

wherein -B is selected from the group consisting of CR&#39;&#39;&#39;&#39;Rv and CHR&#39;&#39;-A in which R&#39;&#39; is H or C6H5, A is a C1-C3 alkyl group or a single bond when R&#39;&#39; is C6H5, R&#39;&#39;&#39;&#39; and Rv which may be identical or different represent H, CH3, C2H5 p-F-C6H4 -R&#39;&#39;&#39;&#39;&#39;&#39; and R&#39;&#39;&#39;&#39;&#39;&#39;&#39;&#39;, which may be identical or different, represent H, a halogen atom, preferably F Cl or Br, a C1 5 alkyl group, CF3, SCH3 SOCH3, SO2CH3, OCH3, OH, C6H5 or a substituted phenyl group. -Rvi represents H, a C1 5 alkyl group, an aryl group, an aryl group the aromatic moiety of which is substituted by one or more CH3, CF3 or halogen atoms, a cycloalkyl group, OH, a C1 6 alkoxy group, an aryloxy group, an aryloxy group the aromatic moiety of which is substituted, a cycloalkyloxy group, a NR3R4 group, a NHCH2-CH2NR3R4 group or a O-alkylene-NR3R4 group. -Y&#39;&#39; represents OH, lower alkoxy having preferably from 1 to 4 carbon atoms, NR3R4, NHCH2CH2NR3R4 or O-alkylene-NR3R4; -X&#39;&#39; represents O or NORo; -Ro represents H, lower alkyl having preferably from 1 to 5 carbon atoms, CH2CH2NR3R4 or CH2CHOHCH2OH; -R3 and R4, which may be identical or different, represent H, lower alkyl having from 1 to 5 carbon atoms, a C3 7 cycloalkyl group preferably a C5 6 cycloalkyl group, an aryl group, an aryl group the aromatic moiety of which is substituted by one or more halogen atoms or CF3 or CH3, R3 and R4 considered together being able to form with the nitrogen atom to which they are bonded a group selected from group consisting of A. 5- TO 7- MEMBERED HETEROCYCLIC RING WHICH MAY CONTAIN A SECOND HETEROATOM SELECTED FROM O, S and N and which may be substituted, and B. AN AMIDE RADICAL ISSUING FROM LYSINE OR CYSTEINE. This invention concerns phenoxy-alkyl carboxylic compounds of the formula

United States Patent [191 Mieville Sept. 23, 1975PHENOXY-ALKYL-CARBOXYLIC ACID DERIVATIVES AND THE PREPARATION THEREOFInventor: Andre Mieville, Chemin de Pierre-Fleur 7, 1000 Lausanne,Switzerland Filed: Jan. 24, 1973 Appl. No.: 326,188

Related US. Application Data Continuation-impart of Ser. No. 8,07], Feb.2, 1970.

Foreign Application Priority Data Jan. 31, 1969 Switzerland 1517/69 Aug.28, 1969 Switzerland 13022/69 US. Cl. 260/247.2 B; 260/239 BF; 260/243B; 260/247.2 A; 260/247.7 S; 260/293.73; 260/293.78; 260/268 R;260/293.8; 260/326.43; 260/470; 260/471 R; 260/473 G; 260/473 S; 260/476R; 260/515 H; 260/516; 260/517; 260/519; 260/521 R; 260/559 T; 260/559B; 260/558 A; 260/592; 424/246; 424/248; 424/263 Int. Cl. C07D 295/04Field of Search 260/247.2 A, 247.7 S, 268 H, 260/293.76, 576, 473 G,293.78, 247.75, 558 A, 239 BF This invention concerns phenoxy-alkylcarboxylic ABSTRACT compounds of the formula wherein -B is selected fromthe group consisting of CR"R and CHRA in which R is H or C H A is a C -Calkyl group or a single bond when R' is C H R" and R which may beidentical or different represent H, CH C H p-F-C H R" and R", which maybe identical or different, represent H, a halogen atom, preferably F C1or Br, a C alkyl group, CF SCH SOCH SO CH OCH OH, C H or a substitutedphenyl group. R" represents H, a C alkyl group, an aryl group, an arylgroup the aromatic moiety of which is substituted by one or more CH CFor halogen atoms, a cycloalkyl group, OH, a C alkoxy group, an aryloxygroup, an aryloxy group the aromatic moiety of which is substituted, acycloalkyloxy group, a NR R group, a NHCH -CH NR R group or aOalkyleneNR R group. Y represents OH, lower alkoxy having preferablyfrom 1 to 4 carbon atoms, NR R NHCH CH NR R or OalkyleneNR R Xrepresents 0 or NOR,,; R represents H, lower alkyl having preferablyfrom 1 to 5 carbon atoms, CH CH NR R or CH CHOHCH OH; R and R.,, whichmay be identical or different, represent H, lower alkyl having from 1 to5 carbon atoms, a C cycloalkyl group preferably a C cycloalkyl group, anaryl group, an aryl group the aromatic moiety of which is substituted byone or more halogen atoms or CF or CH R and R considered together beingable to form with the nitrogen atom to which they are bonded a groupselected from group consisting of a. 5- to 7- membered heterocyclic ringwhich may contain a second heteroatom selected from O, S and N and whichmay be substituted, and b. an amide radical issuing from lysine orcysteine.

7 Claims, N0 Drawings PHENOXY-ALKYL-CARBOXYLIC ACID DERIVATIVES AND THEPREPARATION THEREOF This is a continuation-in-part of my copending U.S.Application Ser. No. 8071, filed Feb. 2, 1970. This invention which is acontinuation in part of my copending US. Pat. Application Ser. No. 8071filed on Feb. 2, 1970 is concerned with phenoxy-alkyl-carboxyliccompounds useful in therapeutic. This invention concerns phenoxy-alkylcarboxylic compounds of the formula wherein B is selected from the groupconsisting of CRR and CHR'-A in which R is H or C l-i A is a C C alkylgroup or a single bond when R is C H R and R which may be identical ordifferent represent H, CH C H C H pFC H R and R", which may be identicalor different, represent H, a halogen atom, preferably F, C] or Br, a Calkyl group, CF SCH SOCH SO CH OCH OH, C H or a substituted phenylgroup. R" represents H, a C, alkyl group, an aryl group, an aryl groupthe aromatic moiety of which is substituted by one or more CH CF orhalogen atoms, a cycloalkyl group, OH, a C alkoxy group. an aryloxygroup, an aryloxy group the aromatic moiety of which is substituted, acycloalkyloxy group, a NR R group; a NHC1-l ---Cl-l l lRg,R group or aO-alkyleneNR R. group.

Y' represents OH, loweralkoxy having preferably from 1 to 4 carbonatoms, NR R NHCH CH NR R or Oalkylene--NR R X represents or NOR,,;

- R represents H, lower alkyl having preferably from 1 to carbon atoms,CH CH NR R or CH CHOHCH OH;

R and R,, which may be identical or different, represent H, lower alkylhaving from 1 to 5 carbon atoms, a C cycloalkyl group preferably a Ccycloalkyl group, an aryl group, an aryl group the aromatic moiety ofwhich is sustituted by one or .7 Compounds corresponding to formula Ican be used as therapeutic agents. Theyac't in particular on the central nervous system. or as anti-inflammatory or normolipemiant agentsand can be used in therapeutic medicines as analgesic,anti-inflammatory, pyschopyrrolidino,

tropic. cardiovascular, normolipemiant, hypocholesterolemiant orantitussivc ingredients.

Consequently. the invention further provides a therapeutic compositioncontaining at least one compound of the invention. as an activeingredient in association with a pharmaceutically acceptable carrier.diluent or coating.

The term alkyl here means a straight branched hydrocarbon chain. Theterm alkoxy means a straight or branched hydrocarbon chain which isbonded to an oxygen atom by a single bond Among the alkoxy groupsaccording to thisinvention. the following simplest ones can bementioned: methoxy. ethoxy. propyloxy, isopropyloxy, butyloxy,isobutyloxy, tertiobutyloxy.

The preferred cycloalkyl groups are cyclopentyl. cyclohexyl and A 1,2cyclohexenyl. The preferred cycloalkyloxy groups are cyclopentyloxy,cyclohexyloxy and Al,2 cyclohexenyloxy.

The term Oalkylene-NR R which is also described as aminoalkyloxy,represents a group consisting of a divalent straight or branchedhydrocarbon chain which is between an oxygen atom and a NR R groups.Preferably the alkylene moiety comprises from 1 t0 6 carbon atoms. Amongthe preferred O-alkylene- NR R groups the following ones can bementioned: Aminoethoxy, aminopropyloxy, aminoisopropyloxy, monoanddialkylaminoethoxy, monoand dialkylaminopropyloxy, monoanddialkylaminoisopropyloxy, piperidinoethoxy, azepinoethoxy,morpholinoethoxy, piperazinoethoxy, N'- methylpiperazinoethoxy,pyrrolidinoethoxy. piperidinopropyloxy, piperidinoisopropyloxy,azepinopropyloxy, azepinoisopropyloxy, piperazinopropyloxy,

.piperazinoisopropyloxy, morpholinopropyloxy, morthi- N'-pchlorophenylpiperazinopropyloxy and N'-pchloro-.

phenylpiperazinoisopropyloxy.

Examples of groups represented by NR R are amino, monoand dialkylamino,morpholino, thiomorpholino,

piperidino, i azepino, N-pchlorophenylpiperazino, N-methylpiperazino,piperazino, 4-methyl-piperidino, anilino, N-methylanilino,2,3-dimethyl-anilino, p-chloroanilino, o-

trifluoromethylanilino, p-trifluoromethyl-anilino, cy-

clohexylamino and cyclopentylamino groups and analogs thereof.

The preferred halogen atoms are fluorine, chlorine and bromine.

The aryl group of R"", R", R and R, can be substituted by one or more F,Cl, Br, CF and CH The preferred ones according to this invention arephenyl, pchlorophenyl and p-fluorophenyl.

Between the compounds corresponding to formula 1 two kinds of productscan be distinguished:

1. the p-carbonyl-phe noxy-alkyl-carboxylic acids and derivativesthereof which result: a a..from transforming'the p-oxo group into oximex NORM I i b. from transforming the carboxylic acid group into ester andamide groups, and,

c. from transforming both the p-oxo group into oxime and the carboxylicacid group into ester and amido groups; and,

2 the p-carboxy-phenoxy-alkyl-carboxylic acids, hereafter called diacidsand derivatives thereof which result from the transformation of one orthe both carboxylic acid groups into ester and amide groups.

Among the Compounds of the p-carbonyl" type. R represents H. C,C alkyl,aryl preferably C H pClC.,H and p FC ,-H,,.

Among the diacid type R" represents OH, C -C alkoxy, aryloxy preferablyphenoxy and pchlorophenoxy, cycloalkyloxy preferably cyclopen tyloxy,cyclohexyloxy, Al,2 cyclohexenyloxy, NR R Methods for preparingcompounds of the formula I are given below, these methods which concernthe causes where B is CR"R can also be used when B is CHRA.

The para-carbonyl compounds of formula I in which X is an oxygen atomand Y is a hydroxy group or a C alkoxy group may be prepared by reactinga parahydroxybenzoyl compound of the formula in which R, R and R"" aredefinedas above with a halogen compound of the formula PROCEDURE APreparation of acids, esters and amides of formula I, in which R is ahydrogen atom X is an oxygen atom a. A p-hydroxyphenyl derivativehavingthe formula (Ila) in which R, is a hydrogen atom or an alkyl or arylgroup, particularly a p-chlorophenyl group, is reacted with an(Jr-halogenated acid of the formula R"CHClCOOH (Illa) in order to obtainrespectively a compound of the formula' (lVa) b. When R represents ahydrogen atom of an alkyl group, compound IVa may be esterefied usingmethyl or ethyl alcohol; the ester obtained may be condensed with anappropriate amine to produce a desired amide of formula I, ortransesterified to synthesize an ester of formula I, other than thosealready mentioned in procedures A (a) and a (12).

c. When R representsan arylradical, compound [Va may be converted bymeans of SOCl or PC1 into the corresponding acid chloride which may bereacted'with an appropriate amine, alcohol or amino alcohol, inaccordance with a method .known per se, in order'to obtain respectivelya desired amide, ester or amino ester of formula I.

d. Compound lVh may be condensed with an appropriate amine in accordancewith a method known per se to produce a desired amide of formula I orcompound lVh may be transesterified to prepare other esters of formulaI.

PROCEDURE A,

order to obtain respectively a compound of the formula b. Compound Vlucan be esterified by means of a lower alcohol. for instance to givemethyl. ethyl orisopropyl ester. particularly when R is an alkyl group.

c. Ester Vlb can be amidified or transesterified. in accordance withmethods known per se to produce respectively an amide or other ester ofthe formula I.

d. When R is an aryl group; compound Vla may be converted into thecorresponding acid i chloride by means of SOClor PCl and then. ifdesired, the acid chloride may be reacted with an appropriate amine.alcohol or amino-alcohol to produce an amide, ester or amino esterrespectively of the formula I.

PROCEDURE Preparation of aldoximes and ketoximes of formula I. i.e.compound of formula I in which X NOH or NOR from the compound of formulaI. in which X NOH, by the following reactions:

-NOH -N LBu-OK The following examples are given to illustrate theinvention.

EXAMPLE I 4-Acetyl-3-thiomethyl-phenoxyacetic acid a. Preparation ofZ-thiomethylacetophenone This step is effected in accordance with apseudo Fries" operation; m-thiomethyl-phenol and acetyl chloride aresuccessively added at 0C to a solution of AlCl 4-hydroxyin nitrobenzene(or a suspension of MCI; in ligroine or dichloroethylene); the resultingmixture is kept at C for 17 hours. and hydrolyzed;4-hydroxy-2-thiomethyl-acetophenone is then isolated by extraction usingdilute sodium hydroxide and washing with hexane. Its melting point is168C.

b. 4-acetyl -3-thiomethyl-phenoxyacetic acid A mixture of l mole of4-hydroxy -2-thiomethyl acetophenoncf 2.2 moles of NaOH. 1.2 mole ofClCH CO-;H and 1300 cc of water, is refluxed for 7 hours. 2

After acidification and extraction with NaHCO followed by a secondacidification. 4-acetyl-3-thiomethylphenoxyacetic acid is isolated. Itsmelting point is 245C.

EXAM PLE 2 Ethyl pisobutyryl-phenoxy-acetatc CH--C0- n c EXAMPLE 3N-(p-Propionyl-phenoxyacetyl) -morpholine This example illustrates theprocedures A (h) and A (d) described above.

a. Methyl p-propionyl-phenoxyacetate 1 mole of p-propionyl-phenoxyaceticacid is refluxed during 10 hours, with 100 cc of MeOH and 300 cc ofCHCL, or CH CI in the presence of sulfuric acid. The resulting mixtureis poured into water. The desired 'ester remains in the organic phase.It is washed once with dilute NaOH, then twice with water. Pure methylp-propionyl-phenoxyacetate is thus isolated. with a yield of above 9071.MP 59C.

h) aa- O-CI'h-CO-N 1 mole of the ester obtained in step (a) is refluxedfor 8 hours with 2.5 moles of morpholine. Then, 1 volume of water isadded, and the product is left to crystallize in the cold state. Themorpholine amide is filtered off and recrystallized from alcohol (yield71; melting point: 88C).

EXAMPLE 4 N-(p-benzoylphenoxyacetyl)-piperidine This example illustratesA (0) described above The piperidinoamide of p-benzoylphenoxy aceticacid is obtained by treating 1 mole of p-benzoylphenoxy acetic acidchloride with 2 moles of piperidine in benzene.

EXAM PLE N-(p-[1-isonitrosopropyl]-phenoxyacetyl)piperidine 1 mole of1-(p-propionylphenoxyacetyl)-piperidine is refluxed for 5 hours with 1.1mole of NH OH, HCl and 1.05 mole of pyridine. The desired oxime isprecipitated in water and recrystallized from alcohol. lts melting pointis 144C.

EXAMPLE 5 bis Semi-industrial preparation of N- (p-1-nitrosoethyl-phenoxyacetyl )-piperidine NOH a. Preparation ofp-acetylphenoxyacetic acid p-hydroxy-acetophenone is treated withchloroacetic acid in aqueous solution in the presenceiof sodiumhydroxide. The desired acid is then isolated from its sodium salt in atotal yield of 8082%, excess of phydroxy-acetophenone having beenextracted with methylene chloride.

b. Preparation of methyl p-acetylphenoxy-acetate A mixture of 80 g ofthe acid obtained in step (a) and 200 ml of methyl alcohol in 600 ml ofdichloromethane is refluxed in the presence of sulfuric acid. Thedesired ester is isolated in accordance with a method known per se, andrecrystallized.

When the refluxing period is 12 hours the ester is obtained with ayieldof 70%.

When the refluxing period is 18 hours. the yield for this ester is 85%.

c. Preparation piperidine The procedure described in example 3 isfollowed using thoroughly dried piperidine. The desired amide isobtained with a yield of 80%.

d. Preparation of N-(p-[1-isonitrosoethyl]-phenoxyacetyU-piperidine Theprocedure described in example 5 is followed using technicalhydroxylamine of 98% purity in place of 100% pure hydroxylamine, andalcohol adulterated with methanol in.place of the absolute alcohol. Thedesired product is obtained in a yield of 75%. l

of N-(p-acetyl-phenoxy-acetyl)- In semi-industrial synthesis, to achievebetter yields, 5

ination of excess of p-hydroxyacetophenone is effected by washing withsodium hydroxide.

By using theprocedure B (h) described above in place of step.(d)corresponding oxime compounds in which R,,- is CH CH CHOH-CH OH. or CHCH NR R where NR R is N(CH;,) N(C H,,) pyrryl. pyrrolidyl. pipcridyl, ormorpholyl are prepared.

EXAMPLE 6 v Preparation of para-(4-chlorobenzoyl)-phenoxyisobutyric acid1 mole of 4-hydroxy-4'-chlorobenzophenone is dissolved in anhydrousacetone and then 5 moles of powered sodium hydroxide is added. Thecorresponding sodium phenoxide precipitates. Refluxing is effected, andthen, 1.5 mole of CHCl diluted with anyhydrous acetone is added and theresulting mixture is refluxed for 10 hours. After cooling, water isadded, the acetone is evaporated, the aqueous phase is washed with etherand acidified and the organic phase is redissolved in ether andextracted into a solution of bicarbonate. The bicarbonate solution isthen acidified to obtain the desired acid, having a melting point of185C, with a yield of Esters and amides of the phenoxy-isobutyric acidsprepared in accordance with the procedure of example 6 are produced inaccordance with procedure A described above.

EXAMPLE 7 lso-propyl p-( 4-chlorobenzoyl )-phenoxy-isobutyrate 1 mole ofthe acid obtained in example 6 is converted Since traces of SO -(whichhas a bad smell) may be obtained from the thionyl chloride, it ispreferable to avoid this disadvantage by carrying out the esterificationdirectly.

Using procedure B described above, isobutyric acids,

and esters and amides thereof prepared in example 6 are connected to thecorresponding oxime compounds.

By using the methods described above in examples 1-7 the followingcompounds were obtained.

N'-(4-chlorophcnyl)-N-(p-acetylphenoxy-acetyl)- piperazine (meltingpoint C) N-(p-acetylphenoxy-acetyl(-morpholine point 1 12C) (melting1(p-acetylphenoxy-acetyl-4-methyl-piperidine (melting point 60C)N-(p-acetylphenoxy-acetyl)-azepine (melting pointN-(p-acetylphcnoxyacctyl)-dicthylaminoethylamine (melting point 75C) N-(p-formylphcnoxy-acetyl )-piperidine (melting point 96C) N-(p-acetylphenoxy-acctyl )-piperidine (melting point 97C)N-(p-isonitrosomethyl-phenoxyacetyl)-morpholine (melting point 169C) 7p-[1-isonitrosoethyl]-phenoxy-acetic said.

ethyl p-[1-isonitrosoethyl]-phenoxyacetate (melting point 103C) 4 N-(p-[l-isonitrosocthyl]-phenoxy-acetyl )-piperidine (melting point 168C)N-(p-[1 isonitrosoethyl]-phenoxy-acetyl)- morpholine (melting point145C) 1-(p-[ l-isonitrosoethyl ]-phenoxy-acetyl )-4-methylpiperidine(melting point 166C)l-(p-[1-isonitrosoethyl]-phenoxy-acetyl-4-(pchlorophenyl)-piperidine(melting point 194C) N-( p-[ l-isonitrosoethyll-phenoxy-acetyl)-azepine(melting point 134C) The diacid of formula 1 in which R and Y are bothhydroxy groups may be prepared in accordance with the invention by (a)reacting p-hydroxybenzoic acid which has the formula COOH 1 with ahalogeno carboxylic acid having the formula Hal-C-COOH in which Halrepresents a halogen atom in an aqueous alkaline medium under reflux,and (h) precipitating the resulting diacid in an acidic medium.

It is preferred to use one mole of p-hydroxy benzoic acid per mole ofthe halogeno carboxylic acid. The compounds of formula 1 in which atleast one of R and Y is other than hydroxy] can be prepared inaccordance with the invention by converting at least one of the acidfunctions of the diacid into an ester or amide function by a methodknown per se for convert- 1 ing carboxylic acid groups to ester or amidegroups.

The diacid. which has the formula VII' t I v ci c0 o-i-cooc n x I RI!!!can be used directly:

can be synthesized in accordance with method c) or else by the action ofethyl bromoacetatez T! BrCC0 C- H on a para-carboxyl-hydroxyphenone ofthe formula HO- OOH in a heterogenous alkaline medium.

From the monoesters of the invention, particularly those of formula V111above, there can be obtained, by

using a method known per se. monoamides of the invention, e.g. of theformula oracid monochlorides, e.g. of the formula l1 12 The acidmonochlorides can in turn be converted into can be converted to an amideester of the invention, symmetrical and asymmetrical diesters andamideeg. of the formula esters of the invention. e.g. of the formulaRilr Xlll

Finally, a symmetrical or asymmetrical diester of the 5 invention, e.g fth f l By a simple modification of the reaction sequences describedabove it is possible to obtain the compounds of the invention in whichone of the R'f -CO and COY g p v group is an amin o ester group and theother of the R"" 2O C O- and -cov is an amide group. any substituents onthe nitrogen The following examples are given to illustrate theinvention EXAMPLE 9 N-( p-carboxyphenoxy-acetyl )piperidine Operation isin accordance with the following reaction scheme:

The amide ester product can be reacted with any EXAMPLE llN-(p-carboxyphenoxy-acetyl)-piperidine coded as No.

a. Ethyl p-carboxyphenoxy-acetate l mole of ethyl bromoacetate isreacted with 1 mole of p-hydroxy benzoic acid in the presence of 2 molesof K CO in acetone. methyl-ethylketone. dioxan or tetra-hydrofuran, for48 hours, at the reflux temperature of the organic solvent to obtainethyl p-carboxyphenoxy-acetate.

b. N-(p-carboxy-phenoxy-acetyl) piperidine The preceeding ester l'mole)is heated under reflux with piperidine (3 moles) in a chlorinatedsolvent, for

l 6 hours. Water is added to precipitate N-(p-carboxyphenoxy-acetyl)piperidine after condensation is complete.

EXAMPLE 12 -N-(p-ethoxycarbonyl-phenoxy-acetyl) piperidine coded as No99 Ethyl p-carboxy-phenoxy-acetate is esterified in ethanol andchloroform in the presence of sulphuric acid.l-(p-ethoxycarbonyl-phenoxy-acetyl)-piperidine is obtained bycondensation of l mole of the resulting diester (ethylp-ethoxycarbonylphenoxy-acetate) with 3 moles of piperidine in an inertsolvent for 7 hours at the boiling temperature of said solvent.

According to the methods described above in examples 9-l 2 the followingcompounds were prepared.

p-carboxamido-phenoxy-acetic acid. (melting point ethylpcarboxamido-phenoxy-acetate (melting point 143C)p-hydroxycarbonyl-phenoxy-acetic point 282C) ethylp-ethoxycarbonyl-phenoxy acetate (melting point 32C)N-(p-carboxyphenoxyacetyl)-morpholine point 183C) What is claimed is:

acid (melting (melting l. A compound of the formula R"--C- -O-BCOY' (I)NOH wherein B is selected from the group consisting of CR"R and CHR'A inwhich R is H or -H A is a C -C alkyl group, R" and R may be identical ordifferent and represent H, CH C H R and R"" may be identical ordifferent and represent H. F, Cl or Br or a C,C,, alkyl group;

R" represents H or a C alkyl group;

Y represents NR R or O-alkylene-NR R wherein R and R may be identical ordifferent and represent H, lower alkyl having from 1 to 5 carbon atoms,a C cycloalkyl group or R and R considered together form with thenitrogen atom to which they are bound a member selected from groupconsisting of a 5- to 7- membered heterocyclic ring which may beinterrupted with a second heteroatom selected from 0. Sand N and whichmay be substituted with a methyl group.

2. A compound according to claim 1 in which NR R is amino, mono ordialkylamino, morpholino, thiamorpholino, pyrrolidino, piperidino,azepino. piperazino, N-p-chlorophenyl-piperazino, N-methylpiperazino, 4-

methylpiperidino. anilino. 2,3-dimethyl anilino, pchloroanilino,o-trifluoromethylanilino, ptrifluoromethylanilino. cyclohexylamino,cyclopentylamino, a N-methylanilino.

3. A phenoxy-alkyl carboxylic acid according to claim 1 in which Y'represents OalkyleneNR R wherein said alkylcne group contains 1-6 carbonatoms.

4. A phenoxy-alkyl carboxylic acid according to claim 1 in which Y is NRR cetyl' piperidine. I

7. A phenoxy-alkyl carboxylic compound according to claim 1 which is N-(p[l-isonitrosoethyH- phenoxyacetyl-morpholine.

1. A COMPOUND OF THE FORMULA
 2. A compound according to claim 1 in whichNR3R4 is amino, mono or dialkylamino, morpholino, thiamorpholino,pyrrolidino, piperidino, azepino, piperazino,N-p-chlorophenyl-piperazino, N-methylpiperazino, 4-methylpiperidino,anilino, 2,3-dimethyl anilino, p-chloroanilino,o-trifluoromethylanilino, p-trifluoromethylanilino, cyclohexylamino,cyclopentylamino, a N-methylanilino.
 3. A phenoxy-alkyl carboxylic acidaccording to claim 1 in which Y'' represents O-alkylene-NR3R4 whereinsaid alkylene group contains 1-6 carbon atoms.
 4. A phenoxy-alkylcarboxylic acid according to claim 1 in which Y'' is NR3R4.
 5. Aphenoxy-alkyl carboxylic compound according to claim 1 which isN-(p-(1-isonitrosopropyl)-phenoxy-acetyl)-piperidine.
 6. A phenoxy-alkylcarboxylic compound according to claim 1 which isN-(p-(1-isonitrosoethyl)-phenoxyacetyl-piperidine.
 7. A phenoxy-alkylcarboxylic compound according to claim 1 which isN-(p(1-isonitrosoethyl)-phenoxyacetyl-morpholine.